Infection with Trypanosoma cruzi, the parasite responsible for acute American trypanosomiasis (Chagas' disease) and chronic Chagas' cardiomyopathy is characterized by persistence of the organism and indications that the host immune defense system is inihibited. Evidence of disordered immunoregulation is seen in the autoimmune manifestations which accompany and may be responsible for pathologic features of the disease. We have found an association between a single gene (1pr) which controls for autoimmune disease in four strains of mice and for susceptibility to T. cruzi infection. Mice with the gene show high parasitemias inevitably accompanied by death; their congenic partners have much reduced parasitemias and usually survive infection. This immunogenetic link between autoimmunity and susceptibility to T. cruzi is reinforced by similar findings in recombinant inbred BXSB mice; male animals with a Y chromosome-associated autoimmune disease are susceptible while females lacking the gene survive. The two other autoimmune strains,, Palmerston North and NZB/BINJ also show increased susceptibility. The finding of a genetic link between spontaneous autoimmune disease and susceptibility to an important infectious process characterized by autoimmune phenomena gives evidence of a common immunoregulatory defect. The availability of genetically defined mice provides a basis for controlled studies on the association between the two pathologic processes. We will investigate this association using in vitro and in vivo immunological methods and search for genetically based immunoregulatory defects. We plan to measure anti-parasite and autoimmune serum factors, do serum and cell transfers, and evaluate mortality and parasitemia in additional mouse strains. We will investigate the relationship between sex and susceptibility and continue studies to assess whether the association between T. cruzi and autoimmunity has parallels in other infectious diseases. The objectives of the research are to determine if an understanding of the genetic factors influencing the two processes will have value in the design of a vaccine for Chagas' disease, contribute to knowledge of the immunogenetic relationship of the host's ability to discriminate between self and not-self, and help to define immunoregulatory factors involved in other autoimmune, lymphoproliferative or infectious diseases.